ANTIDIABETIC AGENTS

1
ANTIDIABETICAGENTS

• Jirí Slíva

2
DIABETES MELLITUS

• Multifactorial disease with genetic component
• Main symptoms hyperglycemia, metabolic
  disturbances
• Relative or total absence of insulin ? increase
  of the glucose blood level
• Borderline DM concentration of glucose plasma
  level 7.0 mmol/L fasting and 11.1 mmol/L 2
  hours after the meal

3
TYPE l diabetes (IDDM, insulin-dependent diabetes
mellitus)

• Formerly juvenile diabetes
• LADA (latent autoimmune diabetes in adults)
• Total absence of insulin
• Langerhans islets B-cells lesion (usually caused
  by autoimmune disease) ? infiltration of islets
  with T-lymphocytes
• Antibodies against islets tissue and insulin

4
TYPE ll diabetes (NIDDM, non-insulin dependent
diabetes mellitus)

• Formerly senile diabetes (onset in adulthood)
• Relative absence of insulin
• Levels of insulin could be normal or above or
  below normal
• Insulin-sensitive tissues show a lack of
  insulin-sensitivity or a reduction of insulin
  receptors is supposed
• NIDDM patients are often obese

5
ANTIDIABETIC AGENTS

• DM l. type treatment
• Insulin
• DM ll. type treatment (PAD)
• Sulphonylureas
• Biguanides
• a-glucosidase inhibitors
• Glitazones (thiazolidinediones)
• Glinides etc.

6
INSULIN

• Human insulin
• low molecular protein
• strong electronegative (binding to positively
  charged proteins in circulation and to membrane
  insulin receptors)
• two peptide chains A (21 AAs) a B (30 AAs),
  linked by disulphide bridges
• Structure of human insulin

7
INSULIN

• Proteohormone
• - glucose utilization
• - metabolism of lipids and proteins
• (storage of these basal sources, anabolic
  hormone)
• Lack of insulin
• (either absolute of relative)
• ?DIABETES MELLITUS

8
INSULIN SECRETION

• Daily production 20 40 IU
• Basal secretion (cca 50 )
• - independent on food intake
• - blocks glucose production in liver
• - responsible for fasting euglycaemia
• Stimulated secretion (cca 50)
• - stimulated by food intake
• - regulates postprandial glycaemia

9
INSULIN TREAMENT INDICATIONS

• DM type 1
• Some DM type 2 patients or
• patients with secondary diabetes
• Insulin treatment in DM type 2 patients
• PAD treatment failure
• Allergy to PAD
• Diabetes in pregnancy
• Severe renal or liver insufficiency
• Clinical situations with contemporary
  decompensated diabetes (operation, infection,
  etc.)

10
INSULIN SYNTHESIS

• preproinsulin ? proinsulin ? insulin a C-peptide
  (shows the endogenous insulin secretion)
• Insulin release from pancreatic B-cells each 15
  -30 min

11
HEALTHY
12
DIABETIC PATIENT
13
INSULIN RELEASE FROM B-CELLS

• Controlled by glucose concentration
• a) influx of glucose to the B-cell by GLUT-2
  transporter
• b) metabolism of glucose by glukokinase
• c) increase of ATP concentration in the cell
• d) closure of ATP-sensitive potassium channels
• e) depolarization and opening of
  voltage-sensitive Ca2 channels
• f) degranulation of B-cells and insulin release
  to the extra cellular space

14

15
INSULIN RECEPTORS

• glycoproteins (muscle, adipose tissue)
• two heterodimers linked by disulphide bridges,
  each consists of a- and ß- subunit
• a-subunit extra cellular, binding place for
  insulin
• ß-subunit transmembrane protein with tyrosine
  kinase activity

16

• Figure Insulin-receptor complexes on the cell
  surface cause chemical responses to occur within
  the cell. This figure was reproduced pending
  permission from the authors of Life, 6th Ed
  (Purves et al, 2001).

17
INSULIN EFFECTS

• The main hormone of metabolic processes in
  liver, muscle and adipose tissue
• stimulates anabolic and inhibits catabolic
  processes
• Facilitates gathering of glucose, aminoacids and
  lipids from food
• Acute effect of insulin ?hypoglycemia

18
ACUTE CONSEQUENCES OF INSULIN SHORTAGE

• Lack of insulin in glucose metabolism ?
  hyperglycemia
• Osmotic diuresis ? polyuria
• Renal loss of water, Na and K ? dehydration,
  thirst
• Dehydration ? hypovolemia
• Release of fatty acids ?hyperacidlipidemia

19
INSULIN THERAPY

• The daily dose as low as possible!
• (up to 40 IU / day)
• Shorter-acting insulin
• ? more doses daily
• ? better compensation of DM
• ? using lower daily dose

20
INSULIN THERAPY

• Conventional therapy
• - insulin in one or two daily doses
• (good compensation just in type 2 DM patients)
• Intensified therapy
• - covers basal and prandial need of insulin
• (more doses, better compensation, lower daily
  dose)

21
ANIMAL INSULIN SOURCES

• bovine and porcine pancreas
• ? complicated purification
• Bovine insulin is different from human insulin in
  three amino acids, porcine in one amino acid
• human insulin
• ADVANTAGE less allergic reactions

22
CLASSIFICATION OFINSULIN PREPARATIONS

• According to sources and purity
• According to duration of action

23
CLASSIFICATION OFINSULIN PREPARATIONS

• Sources and purity
• Animal
• Human
• Insulin analogues
• Duration of action
• Short-acting
• Intermediate-acting
• Long-acting
• Combined (mixtures)

24
ANIMAL INSULINS

• Bovine
• Porcine
• Mixtures
• According to level of purity
• Chromatography purified (PUR)
• Highly purified monocomponent (MC)
• (significantly less contaminated)

25
HUMANE INSULINS (HM)

• emp insulin enzyme techniques to modify porcine
  insulin
• crb insulin chain recombinant DNA in bacteria

26
INSULIN ANALOGUES

• short-acting (glulisine)
• intermediate-acting (lispro)
• chain recombinant DNA in bacteria technique
• the penultimate lysine and proline residues on
  the C-terminal end of the B-chain are reversed
• long-acting (glargine, detemir)

27
DURATION OF ACTION

• Short-acting
• - onset 30 minutes, peak 2-4 hours
• Soluble simple insulin
• Lispro
• Intermediate- and long- acting
• - duration of action between 16 and 35 hours
• Semilente (suspension, amorphous insulin zinc)
• Lente (suspension, mixture,amorphous insulin
  zinc, insulin zinc crystals)
• Isophan insulin (NPH)(complex of protamine and
  insulin)
• Ultralente (suspension, poorly soluble insulin
  zinc crystals)
• Combined
• - fixed mixtures (biphasic,..)

28
Time profiles
29
Pharmacokinetics of insulin

• The speed of absorption depends on
  pharmaceutical properties, dosage, and tissue
  perfusion
• Practically no plasma protein binding
• Degradation of insulin
• kidneys (35?40 ), liver (60 ), the opposite in
  exogenous insulin
• biologic half-life 7?10 minutes
• hydrolysis of S-S bridges between A and B chains
  by insulinase
• further degradation by proteolysis

30
Adverse reactions acute

• hypoglycemic reaction in insulin over dosage,
  inadequate caloric intake (less food), higher
  physical activity
• ? sympathetic reaction (sweating, tremor,
  tachycardia, weakness) and
• ? parasympathetic reaction (hunger, nausea,
  clouded vision)
• Hypoglycemic coma
• i.v. glucose (20?50 ml 40 Glu) or glucagon
  (i.m., s.c.), than glucose or sweet drinks p.o.

31
Adverse reactions long-term

• Long term therapy with repeated episodes of
  hypoglycemia (namely in older patients) gt CNS
  disturbances (fuzziness, incoordinated speech,
  bizzare behavior)

32
Insulin application
33
Application forms

• Insulin syrretes
• Special plastic syrretes, volume 1 ml with sealed
  needle
• 1 scale segment 1 IU of insulin
• Single use
• Most common application form (adults)
• Cheap

Note One international unit of insulin (1 IU) is
defined as the "biological equivalent" of 34.7 µg
of pure crystalline insulin. This corresponds to
the old USP insulin unit, where one unit (U) of
insulin was set equal to the amount required to
reduce the concentration of blood glucose in a
fasting rabbit to 45 mg/dl (2.5 mmol/L).
34
Application forms Insulin pens

• Injectors like pen
• Extensible needle
• Perfect for intensified insulin therapy

35
Structure of insulin pen
36
Application forms Insulin pumps

• subcutaneous continual infusion
• highly reliable, digital, miniature
• advantage exchange each 48 hours, comfortable
  for the patient
• disadvantage expensive, repeated measurement of
  glycemia during the day, higher risk of cutaneous
  infection (permanent needle)

37
Inhalable insulin

• currently not available
• previously approved in U.S (Exubera)
• effective, but no better than injected
  short-acting insulin
• it is unlikely to be cost-effective
• in 2011 announced that when applied deep into the
  nostrils may delay the onset of Alzheimer's
  disease

Note under development ? buccal spray, insulin
pills, insulin patch,
38
ORAL ANTIDIABETICDRUGS
39
Oral Antidiabetic Drugs

• Classification of oral antidiabetics
• Sulphonylureas
• Biguanides
• Intestinal glucosidase inhibitors
• Glitazones (thiazolidinediones)
• Glinides
• Gliptins (syn. dipeptidyl-peptidase 4 (DPP-4)
• SGLT inhibitors
• Other antidiabetics
• Incretinoenhancers

40
Oral Antidiabetic Drugs

• insulin sensitizers
• biguanides
• glitazones (thiazolidinediones)
• insulin secretagogues
• sulphonylureas
• fast (short) insulin secretagogues (Glinides)
• incretins and DPP-4 Inhibitors
• Intestinal glucosidase inhibitors
• SGLT inhibitors

41
Biguanides

• Mechanism of action
• peripheral insulin uptake enhancement (skeletal
  muscle,...)
• Main drugs
• metformin
• Adverse effects
• lactate acidosis

42
Glitazones (Thiazolidinediones)

• Mechanism of action
• peripheral insulin receptors sensitization
• targeting peroxisome proliferator-activated
  receptor (PPAR-gamma)
• improving insulin resistance
• Main drugs
• Pioglitazone (Actos)
• Rosiglitazone (Avandia) withdrawn in 2010,
  because of problems with cardiovascular safety)
• Adverse effects
• hepatotoxicity
• congestive heart failure

43
Sulphonylureas

• Mechanism of action insulin secretion
  stimulation
• Main drugs Tolbutamide, Glibenclamide,
  Glipizide, Gliclazide
• Adverse effects hypoglycemia

44
Fast (short) insulin secretagogues glinides

• Mechanism of action
• insulin secretion stimulation (glycaemia
  dependent)
• Main drugs
• repaglinide, nateglinide
• Adverse effects
• hypoglycemia, GIT disturbances

45
x
46
Sulphonylureas vs. glinides
Sulphonylureas Glinides
1) moderate to long-lasting eff. 2) 1x or 2x daily 3) decreased FBG 4) low eff. on the early secretion of insulin 5) low influence of postprandial glycaemic oscilation 6) clinically significant risk of hypoglycaemia (mostly at night) 7) weight gain 24 kg 8) average decrease of HbA1c 1.5 9) lower price short action administration with each meal postprandial decrease of glycaemia improved postprandial secretion of insulin signif. influence of PP glycaemic oscilation low risk of hypoglycaemia lower weight gain average decrease of HbA1c is comparable in repaglinide nateglinide 0.8 9) higher price
47
Intestinal (Alpha) Glucosidase Inhibitors

• Mechanism of action
• decrease of intestinal carbohydrate absorption
• Main drugs
• acarbose
• miglitol
• Adverse effects
• diarrhoe

48
Physiology of incretins
Note GLP-1 Glucagon-like peptide 1 GIP
glucose-dependent insulinotropic polypeptide
Baggio LL, 2007
49
Physiology of GLP-1
Note Glucagon-like peptide 1 (GLP-1)
Drucker D, 2006
50
Physiology of GIP
Note GIP glucose-dependent insulinotropic
polypeptide
Baggio LL, 2007
51
Structure of GLP-1 and incretinomimetics
Drucker D, 2006
52
Gliptins mechanism of action

• sitagliptin, vildagliptin, saxagliptin

- inhibitors of dipeptidyl peptidase-4 (DPP-4)
incretin enhancers gt increased level of GLP-1
GIP
GIP glucose-dependent insulinotropic polypeptide
Lauster CD, 2007
53
Gliptins metformin
HbA Hemaglobin A ITT Intent to treat LAF
Vildagliptin MET Metformin PBO Placebo
Fonseca V, 2007
54
Characteristics and effects of GLP-1 receptor
agonists and DPP-4 inhibitors
Ahrén B, 2011
55
Glycosuric agents
Marsenic O, 2009
56
Glycosuric agents

• dapagliflozin
• SGLT-2 inhibitor

Marsenic O, 2009
57
Petr Potmešil

• Extension of presentation about antidiabetics

58
Possible risk of pancreatic damage after use of
drugs influencing incretinsIncreased incidence
of pancreatitis (?)actually re-assessment of
safety in course by EMA,no change in
recommendations for therapy available at the
moment (published in Mar-2013, details
www.ema.europa.eu)

• DPP-4 inhibitors (inhibitors of
  dipeptidylpeptidase IV)
• Sitagliptin
• Vildagliptin
• Saxagliptin

• Analogues of GLP-1 (glucagone like peptide)
• Liraglutid
• Agonists of receptor for GLP-1
• Exenatid

59
Diabetes comparison of metabolic effects of
insulin and glucagone

• A/ Insulin

• B/ Glucagone

• 1) ? oxidation of glucose and ? gluconeogenesis
• 2) ? synthesis of glycogen and lipids
• 3) anabolic effect

• 1) ? glycogenolysis
• 2) hyperglycaemia

60
Comparison of pharmacokinetic parameters of
sulphonylureas and biguanides

• A/ Sulphonylureas

• B/ Biguanides

• ? binding to plasm. proteins
• ? biotransformation,
• thus contraindicated in patients with severe
  impairment of hepatic/renal function

• do not bind to plasm. proteins
• no extensive biotransformation, elimination
  mainly by renal excretion, thus contraindicated
  in patients with severe impairment of renal
  functions

61
Some treatment options fordiabetic neuropathic
pain

• Tricyclic antidepressants low tolerability
  (antimuscarinic eff.)
• SSRI - limited efficacy sometimes not
  recommended for pain
• SNRI antidepressants (AE disturbed sleep at
  start)
• 1/ venlafaxine (Effectin) ? dose - possible
  hypertension
• 2/ duloxetine (Cymbalta) also approved for
  urinary stress incontinence and GAD (general.
  anxiety disorder)
• Antiepileptic drugs (AE sedation, weight gain)
• 1/ gabapentin (Neurontin)
• 2/ pregabalin (Lyrica), also for GAD, improves
  sleep
• 3/ carbamazepin many interactions with other
  drugs